CZ454399A3 - Derivatives of ›-amino a ›-acidocarboxylic acid, process of their preparation and their use - Google Patents

Abstract

The solution relates to derivatives of β-amino and βacidocarboxylic acid of formula I wherein R 1 is tetrazole or a group of formula a, wherein the individual substituents are specific importance. These derivatives are used to treat diseases, especially those with elevated levels andothelin.

Description

Technical field

The present invention relates to novel carboxylic acid derivatives, processes for their preparation and use.

BACKGROUND OF THE INVENTION

Endothelin is a peptide consisting of 21 amino acids that are synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, endothelin ”or ET refers to one or all isoforms of endothelin. Endothelin is a potential vasoconstrictor and has a potent effect on blood vessel coloration. This vasoconstriction is known to be caused by the binding of endothelin to its receptors (Nature, 332, 411-415, 1988, FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased and abnormal release of endothelin causes arrested vascular contraction in the peripheral, renal and cerebral vessels, which can lead to disease. As reported in the literature, endothelin is involved in a variety of diseases. These include hypertonia, acute myocardial infarction, pulmonary hypertonia, Raynaud's syndrome, stroke, benign prostate hypertonia, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association).

264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med.

322, 205 (1989), N. Engl. J Med. 328, 1732 (1993), Nephron 66,

373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J.

Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996), Nature Medicine 1, 944, (1995)).

At least two endothelin receptor subtypes, the ETa and ETb receptor, are occasionally described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, the substance must,

- 2 one or both of the effects of endothelin that inhibit the binding of endothelin to receptors, antagonize physiological and therefore represent a valuable drug.

SUMMARY OF THE INVENTION

It is an object to prepare endothelin receptor antagonists that bind to ETα and / or ETb receptors. The present invention relates to B-amimo- and B-acidocarboxylic acid derivatives of the formula I

R2 | w-x

AC CH - O ( ^Z ' _of Q

II ζ = γ ^ζ

R ³ R ¹

R ¹ represents tetrazole or a group O il

C — R

in which R has the following meanings: and) residue OR ⁴ where R ⁴ represents: hydrogen. an alkali metal cation, an alkali metal cation soil, physiologically tolerable organic ammonium, such as tertiary C 1 -C 4 -alkylammonium or ammonium

C 3 -C 6 -cycloalkyl, C 1 -C 8 -alkyl, C 1 -C 6 -phenyl which is substituted by one or more of the following nitro, cyano, C 1 -C 4 -alkyl radicals, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyl; C4-a1 alkoxy, mercapto, C1-C4-alkylthio, amino, alkyl), N (C1-C4-alkyl) 2, may be halogen, hydroxy,

NH (C 1 -C 4 C 3 -C 8 -alkenyl or C 3 -C 8 -alkinyl), the following:

9 9 9

- 3 groups may carry one to five halogen atoms,

R ⁴ may furthermore be a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy, C 1 -C 4 -alkyl; C4-1 alkoxy, mercapto, C ₂ -C 4 alkyl 1 -thio, amino, NH (Ci-C4-alkyl), N (C, -C ₄ -alkyl) _2,

b) a 5 membered heteroaromatic bonded by a nitrogen atom such as pyrrole, pyrazolyl, imidazolyl and triazolyl which may carry one to two halogen atoms, or one to two C 1 -C 4 -alkyl or one to two C 1 -C 4 -alkoxy groups,

c) a group (0) _to five II -O- (CH _{2) p} -S-R where k has the value 0, 1 or 2, p is 1, 2, 3 and 4, and R ⁵ represents

C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkyl or phenyl which may be substituted by one or more, for example one to three, of the following radicals :

halogen, nitro, cyano, C 1 -C 4 -alkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) C4-alkyl 1, ₂ , mercapto.

(d) the rest

O

O where R ⁶ means:

• · · · · ·

C 3 -C 6 -alkenyl, C 3 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, the radicals may carry a C 1 -C 4 -alkoxy-, C 1 -C 4 -alkylphenyl radical such as is listed under

C 1 -C 4 -alkyl, these thio- and / or c),

C 1 -C 4 -haloalkyl or phenyl, optionally substituted, in particular as indicated under (c).

The general substituents have the following meanings:

A NR ⁷ R ⁸ or acido,

W and Z (which may be the same or different):

nitrogen or methine, wherein when W and Z are methine, Q is nitrogen,

X nitrogen or CR ⁹

Y nitrogen or CR ¹⁰ ,

Q is nitrogen or CR ¹¹ , wherein when Q is nitrogen then X is CR ⁹ and Y CR ¹⁰ ,

R ² and R ³ (which may be the same or different):

phenyl or naphthyl, which may be substituted by one or more of the following radicals: halo, nitro, cyano, hydroxy, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 -hydroxy 1 C1-C4-haloalkyl, C1-C4alkoxy, phenoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl) 1), N (C 1 -C 4 -alkyl) 2 or phenyl, which may be substituted one or more times, for example, one to three times by the following substituent: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -h C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio or phenyl or naphthyl which are orthostably bound to each other

- 5 by a direct bond, a methyl or ethyl group, an oxygen or sulfur atom or an SO2-, NH- or N-alkyl group,

C 5 -C 6 -cycloalkyl and these radicals may be substituted one or more times with the following substituent: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy,

R ^{7 is} hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkenyl, C 1 -C 5 -alkylcarbonyl, which radicals may be substituted one or more times by substituents: halogen, hydroxy, mercapto , carboxy, nitro, amino, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkyloxy, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkyloxy, C 1 -C 4alkyloxy , C 1 -C 4 -alkoxycarbonyl, C 3 -C 3 -alkylcarbonyl alkyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, C 3 -C 6 -cycloalkyl, heteroaryloxy or heteroaryl, 5- or 6-membered, containing one to three nitrogen atoms and / or sulfur or oxygen atom, phenoxy or phenyl, all of said alkyl radicals being substituted, for example by one halogen, hydroxy, merkapto,

C 1 -C 4 -alkyl, C 1 -C 4 -haloalkylhaloalkyloxy, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, phenyl, or C 1 -C 4 -alkylthio, one or more to three times the substituents: carboxy, nitro, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen , nitro, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C4 alkylthio, carboxy, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2, dioxomethylene or dioxoethylene,

C 3 -C 6 -cycloalkyl and these radicals may be substituted one or more times with substituents: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkyl;

- 6 alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -haloalkoxy, or

R 7 is bonded to R ⁸ via 4 or 5 Cffe groups into 5 or 6 membered rings,

R ^{8 is} hydrogen, C 1 -C 4 -alkyl, or R ⁸ is bonded with R ⁷ via 4 or 5 CH 2 groups to 5 or 6 membered rings,

R ⁹ and R ¹⁰ (which may be the same or different) hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 8 -alkyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, hydroxy, NH 2,

NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) 2

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkenyl, which radicals may be substituted by halogen, hydroxy, mercapto, carboxy, cyano, or CR ⁹ or CR ¹⁰ is with CR ¹¹ bonded to 5 or 6-membered ring,

R ^{11 is} hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyloxy, C 3 -C 6 alkenyloxy, C 3 -C 8 -alkyloxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkyloxy -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 alkyl) 2, hydroxy, carboxy, cyano, amino, mercapto,

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkenyl, which radicals may be substituted one or more times with the following substituents: halogen, hydroxy, mercapto, carboxy, cyano, amino, C 1 -C 4 -alkyl; -C4- and 1-alkoxy, or CR ¹¹ together with CR ⁹ or CR ^{10 form a} 5 or 6 membered alkylene or alkenylene ring, which may be

- 7 substituted with one or two C 1 -C 4 -alkyl groups and in which one or more methylene groups may be replaced by oxygen, sulfur, NH or -N (C 1 -C 4 -alkyl),

The following definitions apply:

the alkali metal is, for example, lithium, sodium, potassium, the alkaline earth metal is, for example, calcium, magnesium, barium, organic ammonium ions are protonic amines such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine,

C 3 -C 6 -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

C 1 -C 4 -haloalkyl may be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, trichloromethyl,

1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl,

C 1 -C 4 -haloalkoxy may be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-fluoromethoxy - chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy,

C 1 -C 4 -alkyl may be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl,

C 2 -C 4 -alkenyl may be linear or branched, such as ethenyl, 1-propen-3-yl, 1-propen-2-yl,

- 8 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2 butenyl,

C 2 -C 4 -alkynyl may be linear, for example, ethynyl, 1-propin-1-yl, 4-yl or 2-butin-4-yl, or branched, such as 1-propin-3-yl, 1-butynyl The C4- and 1-alkoxy may be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy,

C 3 -C 6 -alkenyloxy may be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy.

C 3 -C 6 -alkynyl oxy may be, for example, 2-propyn-1-yl oxy, yloxy, linear or branched, such as 2-butin-1-yloxy or 3-butyne-2Ci-C4-alkylthio it may be linear or branched, such as methylthio, ethylthio, propylthio, 1-methyl ethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-diethyl ethylthio,

C 1 -C 8 -alkylcarbonyl may be linear or straight-chained, such as acetyl, ethylcarbonyl or 2-propylcarbonyl,

C 1 -C 4 -alkoxycarbonyl may be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl,

C 3 -C 6 -alkylcarbonyl may be linear or branched, for example 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl,

C 1 -C 6 -alkyl can be linear or branched, such as C 1 -C 4 -alkyl, pentyl, hexyl, heptyl or octyl, 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9

The C 3 -C 6 -alkenyl may be linear or branched, such as 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl; Buten-4-yl, 2-buten-3-yl, 1-pentene-5

-yl, 1-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl, or

1-octen-8-y1,

C 3 -C 6 -alkynyl may be linear or branched, such as 1-propyn-1-yl, 1-propyn-3-yl, 1-butin-4-yl,

2-butin-4-yl, 2-pentin-5-yl, 3-hexin-6-yl, 3-heptin-7-yl, 2-octin-8-yl,

Halogen is, for example, fluorine, chlorine, bromine, iodine.

A further object of the invention are those compounds from which the compounds of formula I (so-called prodrugs) can be released.

Preferred are prodrugs in which the release takes place under conditions such as exist in the specified organs of the body, such as the stomach, intestine, blood circulation and liver.

Compounds of formula I as well as intermediates for their preparation, such as formulas II and III, may have one or more asymmetrically substituted carbon atoms. Such compounds may be used as pure enantiomers, optionally pure diastereomers, or as mixtures thereof. It is preferred to use one pure enantiomeric compound as the active ingredient.

The subject invention carboxylic acid derivatives for ETa and / or the invention are suitable as defined.

is furthermore the use of the above for the manufacture of medicaments, in particular for the production of ETb receptors. Antagonist compounds as they were in front

The preparation of the acido group is synthesized by the general formula II from the epoxides of the formula, for example, in WO, in which A is III, which can be 96/11914. These compounds with (11a), are as described above.

React with an acid, for example compounds of formula II react with

1: 1 to 1: 7, at 20 to 150, the epoxides of formula III may be sodium acid. For this, with an acid, in a molecular ratio of 0 ° C to the compound of formula IIIa.

R ²

R ¹ + N ₃ Na

H

N, -C-OH

I i

R ³ R ¹

Ila

The reaction may also be carried out in the presence of a solvent. All solvents inert to the reagents used can be used for this purpose.

Examples of such solvents are aliphatic, alicyclic and aromatic hydrocarbons which may optionally be chlorinated, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and trichlorethylene, ether such as di isopropyl ether, dibutyl ether methyl tert-butyl ether, dioxane and tetrahydrofuran, nitriles such as acetonotrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidine, sulfoxides and sulfones such as dimethylsulfoxide and sulfolane.

The reaction is preferably carried out in a temperature range between 0 ° C and the boiling point of the solvent or solvent mixture.

The presence of a reaction catalyst may be an advantage. Possible catalysts are strong organic and inorganic acids. Examples include, but are not limited to, sulfuric acid, hydrochloric acid, trifluoroacetic acids, p-toluenesulfonic acid, boron trifluoride etherate, and rare earth triflates.

Production of the compounds of the invention of formula I in which:

-11 is A acid group (Ia) _r can be carried out, for example, by reacting the carboxylic acid derivatives of formula IIIa in which the substituents are as defined above with a compound of formula IV.

R ²

w- X w- X Ila + R ¹² - ^(Z -> Á H - c- Z = Y R3 R1 Z = Y IV I In formula IV denotes R ^{1 2} halogen or R13-SO2-, wherein R13 can be C 1 -C 4 -alkyl, C 1 -C 4 -alkyl; -C4-haloalkyl or phenyl and pro W, X, Y, Z and Q apply in front these meanings. The reaction is carried out

preferably in an inert solvent with the addition of a suitable base, i.e. a base which causes deprotonation of the intermediate of formula IIIa, in the temperature range from ambient temperature to the boiling point of the solvent.

The compounds of formula IV are known, partially marketable, or can be prepared according to a generally known method. .

Compounds of formula Ia with R ^{1 =} COOH can be obtained directly when the intermediate of formula IIIa in which R ^{1 =} COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of formula IV. Here too, the reaction is carried out in an inert solvent and in a temperature range from ambient temperature to the boiling point of the solvent.

The base may be an alkali metal or rare earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate such as sodium carbonate or potassium carbonate, metal organic compounds such as butyllithium or alkaliamide such as lithium isopropyl amide or lithium amide.

Production of Compounds of the Invention of Formula I wherein A

12 is an amino group on (Ib), starting from compounds of formula Ia. To this end, the compounds of formula Ia are reacted with hydrogen in the presence of a catalyst such as palladium or platinum in a solvent at a temperature of 20 to 100 ° C. Further, compounds of formula Ia can be reacted to a compound of formula Ib in the presence of triphenylphosphine.

R ²

R ² la

H cw- X '/ \\

R ³ R ¹

-> Η, ΝIb

H cw- X \ '

R ³ R ¹

Z = Y

When R ^{1 is} an ester, the amino groups can be alkylated to a compound of formula Ib according to conventional methods or converted to an amide. Subsequently, the ester groups can then be acid or alkaline cleaved to the carboxylic acid.

Compounds of formula II in which A is a substituted amine (IIc) can also be prepared directly from the epoxide of formula III by amine opening. Substances of formula IIc can then be reacted with compounds of formula IV as described above to give compounds of formula I according to the invention.

The compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I in which R @ ¹ denotes COOH, and these are only converted to the activated form as imidazolide and this halogen is then reacted by conventional means. acids, the corresponding H ₂ NSO ₂ R ⁶ . and requires anhydride or a hydroxyl compound of HOR ⁴ or a sulfonamide

This reaction can often be carried out in conventional solvents by addition of a base, and it is possible to simplify the presence of the above. These two steps can also be achieved, for example, by treating the hydroxyl compound or the sulfonamide with a carboxylic acid as a carbodiimide after the water-cleavable agent.

In addition, the compounds of the formula I can also be prepared by starting from salts of the corresponding carboxylic acids,

That is, from compounds of formula I in which R @ ¹ is COR and R @ 3 is OM, wherein M may be an alkali metal cation or an equivalent of an alkaline earth metal cation. These salts can be reacted with a number of compounds of formula RD, wherein D denotes conventional nucleofugic drainage groups, for example halogen such as chlorine, bromine, iodine or optionally halogen, alkyl or halogenoalkyl substituted arylsulfonyl or alkylsulfonyl such as toluenesulfonyl and methylsulfonyl or others. equivalent groups. Compounds of formula RD with reactive substituents D are known or readily obtainable by general expert knowledge. These reactions can be carried out in customary solvents and are preferably carried out with the addition of a base, with the above mentioned being possible. Compounds of formula I in which R ¹ is tetrazole can be prepared analogously to the methods described in WO 96/11914, from the corresponding carboxylic acids (formula I with R 1 = COOH).

In some cases, the use of generally known protecting groups is required to produce compounds of the invention. For example, if A = HOCH 2 CONH-, it may be hydroxy

Skupí at first secured as benzyl ether, which then cleaves to appropriate degrees. Compounds of formula I and II may be obtained in enant i 0- measuring pure form by that with racemic, eventual diastereomeric compounds of formulas I and II classic

racemic resolution with suitable enantiomeric pure bases such as described in WO 96/11914.

In relation to biological activity, preferred carboxylic acid derivatives of the formula I are preferred as pure enantiomers or pure diastereomers or mixtures thereof, in which the substituents have the following meanings:

A NR ⁷ R ⁸ or acido,

W and Z (which may be the same or different):

· * · · · · · ·

- 14 nitrogen, methine, wherein if W and Z are methine, then Q is nitrogen.

X nitrogen or CR ⁹ , Y nitrogen or CR ¹⁰ , Q nitrogen or CR ¹¹ , wherein if 0 is nitrogen, then X is CR ⁹ and Y CR ¹⁰ ,

furthermore those Q to which, in addition to the above conditions, if Q = CR ³¹ , then Y = CR ¹⁰ or X = CR ⁹ .

R ² and R ³ (which may be the same or different):

phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenoxy, C 1 -C4-haloalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or phenyl, which may be one or more times substituted, for example, one to three times the substituents: halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio, or phenyl or naphthyl which are bonded to each other by orthostabiliation through a direct bond with a methylene, ethylene or ethenyien group, an oxygen or sulfur atom or an SO2-, NH- or N-alkyl group,

R ^{7 is} hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkenyl, C 1 -C 5 -alkylcarbonyl, which radicals may be substituted one or more times with a substituent: halogen, hydroxy , mercapto, carboxy, amino, cyano, C 1 -C 4 -alkoxy, C 3 -C 8 alkenyloxy, C 3 -C 8 -alkyloxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene alkoxy, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, C 3 -C 8 -cycloalkyl, heteroaryloxy or heteroaryl; · · · · · · · · · · · · ·

- aryl, 5- or 6-membered, containing one to three nitrogen atoms and / or sulfur or oxygen, phenoxy or phenyl, wherein said aryl radicals may be substituted one or more times, for example one to three times, by halogen, hydroxy, mercapto , carboxy, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH (C1-C4-alkyl), N (Ci -C4-alkyl 12 or C 1 -C 4 -alkyl thio, phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkylthio, dioxomethylene, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 or di oxoethyl ene,

C 3 -C 6 -cycloalkyl, which radicals may be mono- or polysubstituted by halogen, hydroxy, mercapto, carboxy, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkynyl C4-a1 alkoxy, C1-C4-a1 halo, C1-C4-haloalkoxy.

R8 hydrogen,

R ⁹ and R ¹⁰ (which may be the same or different):

hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2,

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and these radicals may be substituted by substituents: halogen, hydroxy, mercapto, cyano, or CR ⁹ or CR ¹⁰ is attached to CR ¹¹ in a 5 or 6 membered ring,

R ^{11 is} hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 1) 2, cyano, C 1 -C 9 9 · 9999

C 16 -C 16 alkyl, C 2 -C 4 -alkenyl, which radicals may be substituted one or more times by halogen, cyano, C 1 -C 4 -alkenyl, or CR ¹¹ together with CR ⁹ or CR ^{10 form a} 5 or 6 membered alkylene or alkenylene a ring which may be substituted by one or two C 1 -C 4 -alkyl groups and wherein one or more methylene groups may be replaced by oxygen, sulfur, NH or -N (C 1 -C 4 -alkyl).

Particularly preferred are compounds of formula I, pure enantiomers, optionally pure diastereomers, or mixtures thereof, wherein the substituents have the following meanings:

AND NR ⁷ R® or acido, W a (Which may be the same or different): nitrogen or methine, if W and OF they are methine, then Q is nitrogen. X nitrogen or CR ⁹ , Y nitrogen or CR ¹⁰ , Q nitrogen or CR. ¹¹ , wherein if Q is nitrogen. then X is CR ⁹ a Y CR ¹⁰ and if Q is CR ¹¹ , then Y Yippee CR ¹⁰ or X is CR ⁹ t

R ² and R ³ (which may be the same or different):

phenyl, which may be substituted by one or more of the following radicals: halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenoxy, C 1 -C 4 -alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 4 -alkyl) 2 or phenyl, which may be substituted one or more times, for example, one to three times by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -ha 1-alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, or • · • •

- 17 phenyl bonds which are orthostabially bound to each other by a direct bond with a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2-, NH- or N-alkyl group,

R ^{7 is} hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkenyl, C 1 -C 5 -alkenylcarbonyl, the radicals of which may be substituted one or more times with substituents: halogen, hydroxy, carboxy, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkyloxy), N (C 1 -C 4 -alkyloxy) C4-alkyl 1, 2, C3-C8 cycloalkyl, heteroaryloxy or heteroaryl, 5- or 6-membered, containing one sulfur atom or oxygen atom, said aryl radicals may be substituted once, for example one to three times by halogen, hydroxy, mercapto, carboxy, cyano,

C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 or C 1 -C 4 -a C 1 -C 4 -alkyl, up to three nitrogen atoms and / or phenoxy or phenyl, wherein or more than one substituent: C 1 -C 4 -alkyl, phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, cyano, C 1 - C4alkyl, C1-C4-haloalkyl, phenoxy, C1-C4-alkoxy, C1-C4alkylthio, dioxomethylene, or dioxoethylene,

C 5 -C 6 -cycloalkyl and these radicals may be substituted one or more times with a substituent: C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,

R8 hydrogen,

R ⁹ and R ¹⁰ (which may be the same or different):

hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl thio, N (C 1 -C 4 -alkyl) 2,

C 1 -C 4 -alkyl, which radicals may be substituted by halogen, or CR ⁹ or CR ¹⁰ is bonded to CR ¹¹ into a 5 or 6 membered ring,

R ^{11 is} hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylalkyl, cyano, C 1 -C 4 -alkyl,

these residues may halogen substituted, be once or more times or CR ¹¹ forms together with CR ⁹ or CR ¹⁰ 5 or 6 č1enný alkylene or alkenylene ring who may be

substituted with one or two C 1 -C 4 -alkyl groups and wherein one or more methylene groups may be replaced by oxygen, sulfur, NH or -N (C 1 -C 4 -alkyl).

The compounds of the invention offer novel therapeutic potential for the treatment of hypertonia, pulmonary hypertension, myocardium, chronic cardiac insufficiency, acute / chronic renal failure angina, renal and pectoral insufficiency, cerebral ischemia insufficiency, subarachnoid atherosclerosis, endotoxic failure organ, intravascular benign prostatic hyperplasia, vascular spasms, cerebral hemorrhage, migraine, asthma, shock, endoxin-induced coagulation, after angiopastia, ischemic and intoxication-induced renal failure or hypertonia, cyclospore-induced renal failure, metastasis and tumor growth, cancers of the prostate, pancreas and gastrointestinal ulcers.

It is a further object of the present invention to provide combination preparations of both endothelin antagonists and novel receptors of Formula I and inhibitors of renal angiotensin systems. Inhibitors of these systems are renal inhibitors, angiotensin II antagonists and especially angiotensin-converting ng-enzyme inhibitors.

Inhibitors may be administered in a common galenic form or separately temporally and spatially.

In terms of dosage and type of application, consideration is given to •

- 19 the same factors as for the respective individual substances.

These combination preparations are particularly suitable for the treatment and prevention of hypertension and the following diseases as well as for the treatment of cardiac insufficiency.

It is a further object of the invention to use the compounds of the invention for photoaffinity labeling of endothelial receptors. Therefore, those compounds of formula I in which A represents ac i do are particularly suitable.

DETAILED DESCRIPTION OF THE INVENTION

The good effects of the compounds can be shown in the following experiments.

Receptor Binding Studies

Cloned human ETα or ETβ receptor-expressed CHO cells were used for binding studies.

Membrane preparation

ETa or ETb receptor expressed CHO cells were propagated in DMEM NUT MIX F12 medium (Gibco, # 21331-020) with 10% warmed calf serum (PAA Laboratories GmbH, Linz, # 2).

A15-022), 1 mM glutamine (Gibco, Sigma No. P-0781). After 48 hours, cells were washed with PBS and incubated for 5 minutes at 37 ° C with trypsin-containing PBS. They were then neutralized with medium and the cells were concentrated by centrifugation at 300 g.

For membrane preparation, cells were adjusted to a concentration of 10 10 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound, Branson Sonifier 250, 40-70 seconds./constant/output 20.

Binding test • · • ·

- 20 For ETa and ETb receptor binding assays, membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 5 mM MnCl 2, 40 µg / ml bacitracin and 0.2% BSA) at a concentration of 50 µm protein in test batch at 25 ° C incubated with 25 pM (125 I) -ETi (ET a receptor assay) or 25 pM (125 I) -ER3 (ETB receptor assay in the presence and absence of the test substance. Nonspecific binding was determined by 10 ^-7 M eti After 30 min, free and bound radioligands were separated by filtration through a GF / B glass fiber filter (Whatman, England) on a Skatron cell concentrator (Skatron, Lier, Norwegen) and the filter was washed with ice-cold Tris HCl buffer, pH 7.4, with 0.2% BSA The radioactivity concentrated on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

In vivo testing of ET antagonists

Male 250-300 g SD mass rats were anesthetized with amobarbit, attached to artificial respiration, vagotomisirized and disintegrated. Arteria carotir and vein jugularis were cathetized.

In control animals, an intravenous dose of 1 µg / kg ET1 results in a significant increase in blood pressure over a longer period.

The test animals were 30 min. test compound (1 ml / kg) was injected intravenously prior to ET1 dose. To determine ET antagonistic properties, changes in blood pressure in test animals were compared to changes in blood pressure in controlled animals.

ET receptor antagonist testing:

Male 250-350 g of a massive rat (Sprague Dawley, Janvier) was orally treated with test substances. 80 minutes later, the animals were anesthetized with urethane and carotis artery (for blood pressure measurement) as well as the vein jugularis were catheterized.

After the stabilization phase, endothelin (20 pg / kg, injection volume 0.5 ml / kg) or ET1 (0.3 pg / kg, injection volume 0.5 ml / kg) are added intravenously. blood pressure under the curve (AUC) To test substances under pressure, the determination of minutes with continuous frequency is obvious and calculated as areas of antagonistic effect

The AUCs of the treated animals are compared to those of the control animals.

The compounds of the invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally) by the usual route. Administration may also be by vapor or nasal spray.

The dosage depends on the age, condition and weight of the patients as well as the type of administration. As a rule, the daily dose of active compound is between 0.5 and 50 mg / kg body weight at oral dosing and between 0.1 and 10 mg / kg body weight at parenteral dosing.

New compounds of galenic application capsules, powder, granules.

they can be used in solid or liquid forms, for example as tablets, dragees, suppositories, solutions, ointments, creams or sprays. These are produced in the usual way. The active ingredients with galenic auxiliary fillers, preservative flow regulators, dispersants, agents, antioxidants agents, plasticizers 1 a, emulsifiers and / or propellants can be processed by conventional means such as tablet binders, tablet disintegrants, crosslinkers, solvents, retarding gases (see H.Sucker et al., Pharmazeutische Technologie, Thieme-Verag, Stuttgart, 1991). The dosage forms obtained normally contain from 0.1 to 90% by weight of active compound. %.

Synthesis examples • 9 9 fr 9 9 99999 9 9

- 22 Example 1:

2-Hydroxy-3-azo-3,3-diphenylpropionic acid methyl ester

To 80 ml of methanol was added 3.8 g (59.0 mmol) of sodium acid and 3.1 g (59.0 mmol) of ammonium chloride. To this suspension was added 5 g (19.7 mmol) of 3,3-diphenyl-2,3-epoxypropionic acid methyl ester and stirred at room temperature for 48 hours. The batch was concentrated, water was added and aqueous was extracted with acetate. They were then dried over magnesium sulphate, the residue was distilled off and purified by chromatography. The organic phase was solvent several times and 1.2 g (4 mmol, 21 S yield) of purified product was isolated.

Melting point: 102-103 ° C ¹ H-NMR (200 MHz): 7.2 ppm (10H, m), 5.1- (1H, d), 3.5 (3H, s),

3.4 (1 H, d).

Example 2:

2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3-acido-3,3-dimethyl-propionic acid methyl ester

930 mg (6.7 mmol) of potassium carbonate, 1.4 g (6.7 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and 2.0 g (6.7 mmol) of methyl ester were added together to 20 ml of DMF. 2-hydroxy-3-acido-3,3-diphenylpropionic acid. The mixture was stirred at 80 ° C for two hours. After cooling, water was added and the mixture was extracted with acetate. The combined organic phases were dried with magnesium sulfate and the solvent was distilled off. 2.9 g of a crude oil was isolated and reacted directly.

Example 3:

2- (4-Methoxy-6-methyl-pyrimidin-2-yl-oxy) -methyl ester •

• · · ·

3-amino-3,3-dimethylpropionate

2.8 g (6.7 mmol) of 2- (4-methoxy-6-methylpyridin-2-yloxy) -3-acido-3,3-methyl ester were dissolved in 20 ml / 40 ml of methanol / acetate. -diphenylpropionic and at the top of the spatula pallaium on carbon is added. After flushing the apparatus with nitrogen and then with hydrogen, the solution was stirred at normal pressure and ambient temperature for 3 hours. After complete reaction, the palladium was filtered off on charcoal and the solvent was distilled off. 2.9 g of crystals were isolated and reacted directly.

Example 4:

2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3-amino-3,3-diphenyl-propionic acid (1-375)

To a mixture of 6.4 mL of dioxane and 3.2 mL of 1 N potassium hydroxide was added 840 mg (2.1 mmol) of 2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) 3-amino-methyl ester. -3,3-Diphenylpropionic and stirred at 80 ° C for two hours. After cooling, water was added, acidified and extracted with acetate. The combined organic phases were dried with magnesium sulfate and the solvent was distilled off. The residue was triturated with ether and 180 mg (0.5 mol, 25% yield) of crystals were isolated.

¹ H-NMR (360 MHz / DMSO / 303K): 7.7 ppm (1H, broad), 7.4 (4H, m), 7.2 (6H, m), 5.9 (1H, broad), 5.1 (1H, s), 3.2 (3H, broad),

2.1 (3 H, s).

¹ H-NMR (360 MHz / DMSO / 323 K): 7.7 ppm (1H, broad), 7.4 (4H, m),

7.2 (6H, m), 5.9 (1H, s), 5.1 (1H, s), 3.2 (3H, s), 2.1 (3H,

s) ·

Example 5:

• • •

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3-acido-3,3-diphenylpropionic acid (1-542)

To 1.1 g (2.5 mmol) of methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-acido-3,3-dimethoxypropionate A mixture of 11 ml dioxane and 5 ml 1N potassium hydroxide solution was added and the mixture was stirred at 50 ° C for three hours. Cooling, water addition and acidification were performed, followed by extraction with ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off, and 900 mg (2.1 mmol, 85% yield) of crystals were isolated.

Melting point: 164-165 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 421

Example 6:

Methyl-2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-acetylamino-3,3-diphenylpropionate

A catalytic amount of DMAP and 1 g (2.4 mmol) of methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionate were dissolved in 10 ml of pyridine. Cool in ice, add 0.26 mL (3.7 mmol) of acetyl chloride dropwise and stir at room temperature for 12 hours. Water was added and the mixture was extracted with ether. The combined organic phases were dried with magnesium sulfate and the solvent was distilled off. The residue was mixed with ether and the compound crystallized (1 g, 2.2 mmol, 90% yield) in a short time. The compound may be further purified.

Example 7:

2- (4,6-Dimethoxy-2-pyrimidinyl oxy) -3-acetyl amino-3,3-diphenylpropionic acid (1-174)

To 1 g (2.2 mmol) of 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-

a mixture of 8.8 mL of potassium was added, and the mixture was acetylamino-3,3-diphenylpropionate, dioxane and 4.4 mL of 1 N hydroxide solution were stirred at 80 ° C for one hour. Cool and add water, followed by extraction with ether. Then the acidification was methyl tert. -butyl ether. The combined phases were dried by distilling off the solvent. The residue was mixed with ether to isolate 640 mg (1.5 mmol, 67% yield) of crystals.

Melting point: 120-121 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 437

Example 8:

made organic

Cyclopentapyrimidin-2-yloxy) methyl 2- (4-methoxy-6,7-dihydro-5H 3-azido-3,3-diphenylpropionate), 2.5 g (10.8 mmol) 4 Methylsulfonylpyrimidine and γ-3-azido-3,3-diphenylpropios were stirred at 60 ° C for three added water, followed by organic phases, dried (solvent and% yield) of the crystals and action.

743 mg (5.4 mmol) of drase methoxy-6,7-dihydro-5H-cyclopenta-2 carbonate 3.0 g (10.8 mmol) of methyl-2-hydroxy:

The mixture was stirred in 20 ml of DMF. Clock. Cooling and extraction with ethyl acetate was performed. Combined with magnesium sulfate, 3.7 g (8.3 mmol, 77) was isolated by decantation and prepared immediately for the next step

Example 9:

2- (4-Methoxy-6,7-dihydro-5H-cyclopentimidin-2-yloxy) -3-azido-3,3-diphenylpropionic acid (1-518)

To 3.7 g (8.3 mmol) of methyl 2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-aceto-3,3-diphenylpropionate was added a mixture of 33 mL dioxane and 17 ml of 1N potassium hydroxide solution and the mixture was stirred four times at 50 ° C for two hours and then at room temperature for 12 hours. Fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

Water and the impurities were extracted with ether. The combined organic phases were dried with magnesium sulfate and the solvent was distilled off. The residue was crystallized with ether / n-hexane, 2.6 g (5 mmol, 60% yield) of crystals were isolated.

Melting point: 143-144 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 431

Example 10:

The following compounds were prepared in the same manner as described in the Examples above

2- (4,6-Dimethoxy-2-pyrimidinyl) -3-amino-3,3-diphenylpropionic acid (1-354)

Melting point: 159-160 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 395

2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyridin-2-yloxy) -3-amino-3,3-diphenylpropionic acid (1-334)

Melting point: 119-120 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 405

2- (4,6-Di-methoxy-2-pyrimidinyloxy) -3-methoxyacetyl amino-3,3-diphenylpropionic acid (1-535)

Melting point: 187-188 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 467

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3- (2,2-dimethylpropylcarbonylamino) -3,3-diphenylpropionic acid (1-388)

Melting point: 187-188 ° C ¹ H-NMR (200 MHz): 7.5 ppm (2H, m), 7.2 (8H, m), 6.7 (1H, s),

6.5 (1H, s), 5.7 (1H, S), 3.8 (6H, s), 2.1 (2H, s), 1.0 (9H, s)

9 9 9 9 9 9 9

9 9 9

99 * «·· 9 9 99 • · ·

- 27 2- (4,6-Di-methoxy-2-pyrimidinyloxy) -3-cyclopropylcarbonylamino-3,3-diphenylpropionic acid (1-227)

Melting point: 206-207 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 463

2- (4,6-Di-methoxy-2-pyrimidinyloxy) -3-p-nitrobenzoylamino-3,3-diphenylpropionic acid (1-541)

Melting point: 219-220 ° C

ESI-MS: M ^& lt ^{; +} & gt ^; = 544

The compounds listed in Table 1 may be prepared in an identical manner or as described in the general section.

PE7B KALENSKÝ

- 28 x ^of 'I II cóTable

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OF of of of of of 33 r i of ζ ζ ζ ζ of of of of of of of OF of of of of mJ Φ Φ φ φ Φ Φ Φ Φ with Φ Φ Φ 2 Φ Φ φ 2 φ 2 Φ Φ Φ 2 Φ Φ 2 Φ Φ 2 2 Φ O 2 2 2 O 2 2 2 Ο 2 Ο 2 with 2 O 2 2 O 2 2 O AND O AND G J of of 1 O 1 O 1 O at O O O Ο Ο Ο υ AT J O O O O O c> AT at Cl O α Φ Φ Ol 2. 1 1 1 of OF of OF OF OF of OF of of of C O of of of O OF OF ζ ζ Ζ ζ OF O O at at at at Cl Cl Cl Cl c> rd rd rd rd > 1 of of of α Φ φ ζ of Φ Φ of Φ of Φ Φ Φ β 2 OJ 2 Φ Φ Φ 2 φ Ρ φ P Φ 2 2 P Φ 2 P 2 2 2 P C 2 O 23 2 2 Ο 2 φ 2 Φ 2 O O Φ 2 O Φ O O 1 O 1 Φ J X C of at at AT of O AT ο WHOSE ο AT at at O O at O Cl Cl Cl at O Cl and of OF OF OF ζ Ζ of *> 2 of C O at of at O ο ζ. ζ ο O of of of of of of of of of of of 1 and 1 CN 1 CN 1 ζ 2 OF OF ζ C O O ο C 1 1 ο 1 1 C 1 H r-l CN 1 of of and Sí of 1 ζ 1 of of of C C β of υ ζ of O O C Φ Φ of ο ζ O Cl Cl 1 P P O 1 ο Cl 1 1 at rd ο 1 P rd > 1 1 1 CN 5> ι 1 1 CN 1 1 1 1 rd C < 1 Φ Φ 1 OF β ζ ζ ζ 1 of of of of of 1 1 β β C of 2 2 of at φ ζ ζ υ of of of of of β of of Φ Φ α of O O of O Ρ ο ο ο of O O O O Φ of of Md Md £ O 1 1 O 1 ο ο 1 O O O at at Md 1 1 1 O Ή • H O rd 1 1 1 Ρ O CN C 4 C J CN rd rd 1 1 α Ό here (Ú 1 CN φ rd rd CN of of of of 1 of go Φ CN 2 of 1a i a of β 2 ζ ζ Ν of at at O O of β β 2 O C O N <2 O φ ο ζ ζ β O O O O O O Φ Φ ω OF 1 O < < O C- F ΪΡ 1 Ρ Ρ Φ O Φ Φ Φ Φ 1 t | | Md 1 1 <* m of mC mC of of of Ν ’ φ φ Ζ of 2 2 2 2 Ν ’ of OF r — 1 r-d rd r- | rd > of of of of m C β β β β Φ rd i-l Φ Φ Φ 1 — 1 rd rd rd rd Φ rd rd rd rd rd rd rd P rd rd -and From > 1 p 5> ί > “1 P P P ζ rO ζ ζ > Ί Md OF > 1 r * í of of > 1 of 1> 1 of 5> i C C β β β β β β β β β β β β β β β β β cn ' α 1 Φ Φ 1 1 1 φ φ φ φ φ 1 Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ OF P fa and P P r-i Q fa and fa AND Ρ Ρ Ρ Ρ Ρ fa AND P P P P P P P P P P P Ν ’ 1 of -Η and OF of of of of of ζ ζ ζ ζ Ζ of of of OF of of of of of of of O C O O O O O O ο ο ο ο Ο O O O O O O O O O O O υ From C. O O O O O O ο ο ο ο ο O O O O O O O O O O O Cl C O O O O O O ο ο ο υ ο O O at O O Cl Cl Cl c> O c> > 0 C rd CN ro Ν ’ uo MD Γ 00 σ ο rd CN ro LD <D r-- 00 O rd CN • Ό N CN CN CM CN CN CN CM CN CN m ro m ro ro ro ro m m m M * 0 Lf LH m LD in in in LD ιό ΙΌ ΙΌ tn ΙΌ LO ΙΌ tn tn in UO uo U0 UO uo n CM H TO H H H H Η Η Η Η η f-d f-d f-d f-d f-d η P f-d f-d f-d H = L

t * 2 2 2 E Γ) 2 2 r) 2 Γ) 2 2 2 2 2 and r; 2 2 Ε Γ j 2 2 2 2 2 2 2 2 Her Φ Φ Φ Φ Φ φ Φ Φ and G G Φ G G Φ G G Φ Φ 2 G Φ Φ Φ G Φ Φ Φ Φ Φ 2 O O with O O G O O G G C Ο G G G C G G G G G > t C d at at AT d 2 O d d d d d ύ d 2 AT AT G ύ AT d d AT at 1 <! at 1 d 1 and φ O Φ Φ . C 1 α Φ Φ C G 2 G G 2 2 G G C and 1 1 AT 1 1 d 1 AND 2 2 1 2 2 l L < 4d 2 1 d d 2 2 1 C 2 2 2 d 2 2 AT AT AT d 2 AT d 2 2 d 2 1 AT d ( 1 1 ř ” and O O r — i γΗ Μ d 1 1 > > 4 3η X 1 d φ d X X φ Φ Φ Φ X 5 d Φ G Φ Φ Φ X Φ X G Φ G Φ Φ G G X and G O G G G Φ G φ ο G Ο G G Ο Ο Φ > C 2 at 2 d d d d d 2 ύ d AT AT AT 2 AT AT d d d 2 2 2 2 2 2 with 2 2 2 d 2 2 2 2 2 2 2 2 2 d d 2 2 2 2 AT 2 2 d AT “Ι- ΟΙ τ— 04 / 1 2 1 2 2 2 and d AT Ο 2 1 1 1 1 1 AT AND 1 1 O rH H 2 1 rH H AND 1 Η 1 1 2 and d X X 2 2 > 1 X and rH > 4 2 2 2 2 1 C C O 2 β β 2 Ϊ> Ί β 2 2 Ο C H Φ Φ d O Φ Φ C β φ Ο Ο d d > 44 44 1 d 44 X C φ X AT d 1 1 C Ή 1 AND X AND 1 rH r- , φ 1 1 X rH 1 1 1 1 AND" 1 Η r-4 3η > , ‘P Φ Φ C > 1 Φ 2 2 Φ 3 1 1 1 AND 2 > > 1 β C WITH G Φ β E 2 2 G C γΗ 2 2 Ο β β Φ and 1 O O 44 Φ O O O O φ 1 1 AT 2 2 1 φ φ X rH 1 1 44 1 at AT 1 X 2 2 1 1 1 ψ X * + - > • H H 1 • H 1 1 Ή 2 2 • Η γΗ rH 1 1 1 X O | Ol Φ 1 Til rd rH 1 Ο Ο τΐ 3η 3η ΦΙ 1 1 ο F" X .and .2 G rH ia > 1 > 1 r-4 d AT Γ β β ga ! «Η γΗ ο d Φ ^ 2 O at X X 32 d Γ * ι Ρ Φ Φ ΟΕ ! AT υ 2 ri 1 1 < •O 1 r P ι i C 4-> X -C 1 Εμ fa WITH X X ΙΦ 1 Ρ ) r II 1 in oT_ OU > * 2 2 oTJ Φ Φ I.E Τ AT AT οι ΟΊΦ 01 2 2 04 / r— | r — 1 r— ( > 1 C C β m Φ Φ Φ 0 l " H H r * 4 X 44 44 r-4 rH rH r-1 Ή Μ γ— | γΗ γ-Μ f-d γΗ X γ-Η γΗ 1— ( 1 — 1 γΗ > > > 1 > 1 3h > 4 3h > 1 3η 3η > 4 3η > 3η 3η 3η 3η C C C C 1 1 1 β β β β β C β β β β β β β β β β β CM and Φ Φ Φ fa fa fa Φ Φ Φ Φ φ φ φ φ Φ Φ Φ Φ φ 0) Φ Φ Φ 0 4- 44 44 44 1 1 * p 1 44 44 44 X X X X X X X X X X X X X X and and 2 2 2 2 2 2 2 2 2 2 and 2 2 2 2 2 2 2 2 2 2 2 H O O O O O O O O O O O ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο 0 O O O O O O O O O O O ο ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο O at at at at at d d at at at υ d AT υ AT AT υ υ υ d d AT υ > c lp it 00 σ O rH 04 / what sr LP KD r- 00 σι ο Γ * Η ΟΙ ΓΌ ιη kO Γ- in in «3« in- in LP LP in in ιη ιΡ LD ιη ΙΡ Ό «Ο Ό ΙΟ ΙΟ Ό LO LD Q lp lp LO LP lp ID lp LP in m m LD m ΙΡ ιΡ m ιη ιη m ιΡ ΙΡ ιη LP LP 0 H H H H M H H H H H H Η Η Η Η Η Η Η Η Η Η Η Η Η

• ·

- 53 Example 11

According to the binding assay described above, receptor binding values were measured for the following compounds.

The results are shown in Table 2.

Table 2

Receptor binding (Ki value)

compound ETa (nM / 1) ETb (nM / l) 1-174 83 > 7000 1-227 225 2800 1-334 600 6400 1-354 50 > 6400 1-375 300 7300 1-388 1000 7000 1-518 14 460 1-535 35 7000 1-541 1000 > 7000 1-542 60 2200

ΡΕΪ3 KALENSKÝ

ATTORNEY AT LAW

Claims (8)

PATENT CLAIMS Β-Amino and β-aci dicarboxylic acid derivatives of formula I R2 A-C-CH-O I I R ³ R ¹ wx h \ £ Z = Y R @ ¹ denotes tetrazole or a group II c — R in which R has the following meanings: (a) radical OR ⁴ where R ⁴ represents: hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic ammonium ion, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkyl, optionally substituted, CH 2 -phenyl, optionally substituted, C3-C8-alkenyl or C3-C8-alkenyl, optionally substituted or phenyl, optionally substituted, (b) a 5-membered heteroaromatic bonded via a nitrogen atom; (c) the group —o— (CHJ _P — s — R ⁵ in which k is 0, 1 and 2, p is 1, 2, 3 and 4; and R5 denotes C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -alkenyl, C 3 -C 8 alkynyl or optionally substituted phenyl. • · • · · · · · · · • * · · · ···· · · · · • · · · • · · · • · «· • · » • · - 55 - ··· · ······· • · · · (d) the rest 0 11 II g -NH — S— II II 0 where R® means: C 1 -C 4 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkynyl cycloalkyl, optionally bearing these radicals C 1 -C 4 -alkoxy-, C 1 -C 4 -alkylthio-O- and / or phenyl the residue being A NR ⁷ R ® or acido. W and Z, which are the same or different: nitrogen or methin, when W and Z are methi n, is Q nitrogen, X nitrogen or CR ⁹ Y nitrogen or CR ¹⁰ , Q nitrogen or CR ¹¹ , taking when is Q nitrogen, then is X CR ⁹ a Y CR ¹⁰ , R2 and R ³ , which are the same or different: phenyl or naphthyl, optionally substituted, or phenyl or naphthyl, which are orthostably bound to each other via a direct bond, a methyl or ethyl group, an oxygen or sulfur atom, or an SO2-, NH- or N-alkyl group, C 5 -C 6 -cycloalkyl, optionally substituted, R ^{7 is} hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkenyl, C 1 -C 5 -alkylcarbonyl, these radicals being optionally substituted, phenyl or naphthyl, optionally substituted, optionally substituted C 3 -C ⁶ -cycloalkyl or R ^{7 is} bonded with R ⁷ by 4 or 5 CH 2 groups to 5 or 6-membered rings, R® hydrogen, C 1 -C 4 -alkyl, or R® is bonded to R ⁷ via 4 or 5 CH 2 groups into 5 or 6 membered rings, R ⁹ and R ¹⁰ which are the same or different: hydrogen, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -alkyloxy, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkyloxy -C4-aylcarbonyl, C 1 -C 4 -alkoxycarbonyl, hydroxy, NH 2, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 alkyl) 2 C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkenyl, these radicals being optionally substituted or CR ⁹ or CR ¹⁰ bonded with CR ¹¹ to a 5 or 6 membered ring, halogen , C 1 -C 4 -alkoxy, C 1 -C 4 -haloC 3 -C 6 -alkylene, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkyloxy alkylcarbonyl, C1-C4-alkoxycarbonyl, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2, hydroxy, carboxy, cyano, amino, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 -alkynyl, C 2 -C 4 -alkynyl, these radicals being optionally substituted, R ^{11 is} hydrogen, and 1 alkoxy, with CR ⁹ or CR 5 or 6 alkenylene ring, or CR ¹¹ together form a membered alkylene or which is optionally substituted and wherein one or more methylene groups may be replaced by oxygen, sulfur, NH or -N (C 1 -C 4 -alkyl), and physiologically tolerable salts and possible enantiomerically pure and diastereoisomerically pure forms. Use of the β-amino and β-acidocarboxylic acid derivatives according to claim 1 for the treatment of diseases. Use of the compounds of formula I according to claim 2 as endothelin receptor antagonists. The use of the β-amino and β-acidocarboxylic acid derivatives according to claim 1 for the manufacture of a medicament for the treatment of diseases in which elevated endothelin levels occur. • 9 • · The use of β-amino and β-acci dicarboxylic acid derivatives according to claim 1 for the treatment of chronic cardiac insufficiency, high blood pressure, pulmonary high pressure, acute / chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer. β-amino acid lineage in combination with systems such as α-acidocarboxylic renal inhibitors Use of the derivatives according to claim 1 of angiotensin angiotensin II antagonists and angiotensin-converting ng-enzyme (ACE) ACE / Neutral Endopeptidase (NEP) and beta-blocking, in particular, mixed blockers. inhibitors, inhibitors and inhibitors 7. Medicinal preparations for oral, parenteral and intraperenteral use, containing, in addition to the usual auxiliary agents, at least one carboxylic acid derivative of the formula I per unit dose. 8. Compounds of formula II R ² A C — CH — OH! ! R ³ R ¹ wherein the radicals R ¹ , R ² , R ³ and A are as defined in claim 1. Use of compounds of formula II R ² A C CH-OH I R ³ R 1 wherein the residues R ¹ , R ² , R ³ and A are as defined in claim 1 as a starting material for the synthesis of endothelin receptor antagonists. «· - 58 • · ·> · * «• < • · · < 10. Structural fragment of the formula R ² H R ³ wherein the residues R ¹ , R ² , R ³ and A as a structural element R ¹ are as defined in claim 1, antagonize hundred endothe1 and new receptors.